Polo-like Kinase Plk2 Is an Epigenetic Determinant of Chemosensitivity and Clinical Outcomes in Ovarian Cancer

Cancer Res. 2011 May 1;71(9):3317-27. doi: 10.1158/0008-5472.CAN-10-2048. Epub 2011 Mar 14.

Abstract

Resistance to platinum- and taxane-based chemotherapy remains a major clinical impediment to effective management of epithelial ovarian cancer (EOC). To gain insights into resistance mechanisms, we compared gene and confirmed expression patterns of novel EOC cell lines selected for paclitaxel and carboplatin resistance. Here, we report that resistance can be conferred by downregulation of the Polo-like kinase Plk2. Mechanistic investigations revealed that downregulation occurred at the level of transcription via associated DNA methylation of the CpG island in the Plk2 gene promoter in cell lines, primary tumors, and patient sera. Inhibitory RNA (RNAi)-mediated knockdown and ectopic overexpression established a critical functional role for Plk2 in determining apoptotic sensitivity to paclitaxel and carboplatin. In drug-resistant human EOC cell lines, Plk2 promoter methylation varied with the degree of drug resistance and transcriptional silencing of the promoter. RNAi-dependent knockdown of Plk2 abrogated G(2)-M cell-cycle blockade by paclitaxel, conferring resistance to both paclitaxel and platinum. Conversely, ectopic expression of Plk2 restored sensitivity to G(2)-M cell-cycle blockade and cytotoxicity triggered by paclitaxel. In clinical cases, DNA methylation of the Plk2 CpG island in tumor tissue was associated with a higher risk of relapse in patients treated postoperatively with carboplatin and paclitaxel (P = 0.003). This trend was also reflected in the analysis of matched serum samples. Taken together, our results implicate Plk2 as a clinically important determinant of chemosensitivity, in support of the candidacy of Plk2 as a theranostic marker to inform EOC management.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboplatin / pharmacology*
  • Cell Division
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • CpG Islands
  • DNA Methylation
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Female
  • G2 Phase
  • Gene Silencing
  • Humans
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics*
  • Paclitaxel / pharmacology*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Transcriptional Activation
  • Transfection

Substances

  • Carboplatin
  • PLK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Paclitaxel
  • Cisplatin